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Lapachone AND NAD+

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https://www.readbyqxmd.com/read/28592850/nad-augmentation-ameliorates-acute-pancreatitis-through-regulation-of-inflammasome-signalling
#1
AiHua Shen, Hyung-Jin Kim, Gi-Su Oh, Su-Bin Lee, Seung Hoon Lee, Arpana Pandit, Dipendra Khadka, Seong-Kyu Choe, Sung Chul Kwak, Sei-Hoon Yang, Eun-Young Cho, Hyun-Seok Kim, Hail Kim, Raekil Park, Tae Hwan Kwak, Hong-Seob So
Acute pancreatitis (AP) is a complicated disease without specific drug therapy. The cofactor nicotinamide adenine dinucleotide (NAD(+)) is an important regulator of cellular metabolism and homeostasis. However, it remains unclear whether modulation of NAD(+) levels has an impact on caerulein-induced AP. Therefore, in this study, we investigated the effect of increased cellular NAD(+) levels on caerulein-induced AP. We demonstrated for the first time that the activities and expression of SIRT1 were suppressed by reduction of intracellular NAD(+) levels and the p53-microRNA-34a pathway in caerulein-induced AP...
June 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28346693/using-a-novel-nqo1-bioactivatable-drug-beta-lapachone-arq761-to-enhance-chemotherapeutic-effects-by-metabolic-modulation-in-pancreatic-cancer
#2
Muhammad Shaalan Beg, Xiumei Huang, Molly A Silvers, David E Gerber, Joyce Bolluyt, Venetia Sarode, Farjana Fattah, Ralph J Deberardinis, Matthew E Merritt, Xian-Jin Xie, Richard Leff, Daniel Laheru, David A Boothman
Novel, tumor-selective therapies are needed to increase the survival rate of pancreatic cancer patients. K-Ras-mutant-driven NAD(P)H:quinone oxidoreductase 1 (NQO1) is over-expressed in pancreatic tumor versus associated normal tissue, while catalase expression is lowered compared to levels in associated normal pancreas tissue. ARQ761 undergoes a robust, futile redox cycle in NQO1+ cancer cells, producing massive hydrogen peroxide (H2 O2 ) levels; normal tissues are spared by low NQO1 and high catalase expression...
March 27, 2017: Journal of Surgical Oncology
https://www.readbyqxmd.com/read/27986568/distinct-responses-of-compartmentalized-glutathione-redox-potentials-to-pharmacologic-quinones-targeting-nqo1
#3
Vladimir L Kolossov, Nagendraprabhu Ponnuraj, Jessica N Beaudoin, Matthew T Leslie, Paul J Kenis, H Rex Gaskins
Deoxynyboquinone (DNQ), a potent novel quinone-based antineoplastic agent, selectively kills solid cancers with overexpressed cytosolic NAD(P)H:quinone oxidoreductase-1 (NQO1) via excessive ROS production. A genetically encoded redox-sensitive probe was used to monitor intraorganellar glutathione redox potentials (EGSH) as a direct indicator of cellular oxidative stress following chemotherapeutic administration. Beta-lapachone (β-lap) and DNQ-induced spatiotemporal redox responses were monitored in human lung A549 and pancreatic MIA-PaCa-2 adenocarcinoma cells incubated with or without dicumarol and ES936, potent NQO1 inhibitors...
January 29, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27960087/leveraging-an-nqo1-bioactivatable-drug-for-tumor-selective-use-of-poly-adp-ribose-polymerase-inhibitors
#4
Xiumei Huang, Edward A Motea, Zachary R Moore, Jun Yao, Ying Dong, Gaurab Chakrabarti, Jessica A Kilgore, Molly A Silvers, Praveen L Patidar, Agnieszka Cholka, Farjana Fattah, Yoonjeong Cha, Glenda G Anderson, Rebecca Kusko, Michael Peyton, Jingsheng Yan, Xian-Jin Xie, Venetia Sarode, Noelle S Williams, John D Minna, Muhammad Beg, David E Gerber, Erik A Bey, David A Boothman
Therapeutic drugs that block DNA repair, including poly(ADP-ribose) polymerase (PARP) inhibitors, fail due to lack of tumor-selectivity. When PARP inhibitors and β-lapachone are combined, synergistic antitumor activity results from sustained NAD(P)H levels that refuel NQO1-dependent futile redox drug recycling. Significant oxygen-consumption-rate/reactive oxygen species cause dramatic DNA lesion increases that are not repaired due to PARP inhibition. In NQO1(+) cancers, such as non-small-cell lung, pancreatic, and breast cancers, cell death mechanism switches from PARP1 hyperactivation-mediated programmed necrosis with β-lapachone monotherapy to synergistic tumor-selective, caspase-dependent apoptosis with PARP inhibitors and β-lapachone...
December 12, 2016: Cancer Cell
https://www.readbyqxmd.com/read/27913299/the-inhibitory-effect-of-beta-lapachone-on-rankl-induced-osteoclastogenesis
#5
Dong Ryun Gu, Joon No Lee, Gi-Su Oh, Hyung Jin Kim, Min Seuk Kim, Seoung Hoon Lee
β-lapachone (β-L) is a substrate of reduced nicotinamide adenine dinucleotide (NADH): quinone oxidoreductase 1 (NQO1). NQO1 reduces quinones to hydroquinones using NADH as an electron donor and consequently increases the intracellular NAD+/NADH ratio. The activation of NQO1 by β-L has beneficial effects on several metabolic syndromes, such as obesity, hypertension, and renal injury. However, the effect of β-L on bone metabolism remains unclear. Here, we show that β-L might be a potent inhibitor of receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis...
January 22, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27790277/increased-cellular-nad-level-through-nqo1-enzymatic-action-has-protective-effects-on-bleomycin-induced-lung-fibrosis-in-mice
#6
Gi-Su Oh, Su-Bin Lee, Anjani Karna, Hyung-Jin Kim, AiHua Shen, Arpana Pandit, SeungHoon Lee, Sei-Hoon Yang, Hong-Seob So
BACKGROUND: Idiopathic pulmonary fibrosis is a common interstitial lung disease; it is a chronic, progressive, and fatal lung disease of unknown etiology. Over the last two decades, knowledge about the underlying mechanisms of pulmonary fibrosis has improved markedly and facilitated the identification of potential targets for novel therapies. However, despite the large number of antifibrotic drugs being described in experimental pre-clinical studies, the translation of these findings into clinical practices has not been accomplished yet...
October 2016: Tuberculosis and Respiratory Diseases
https://www.readbyqxmd.com/read/27608947/nampt-inhibition-synergizes-with-nqo1-targeting-agents-in-inducing-apoptotic-cell-death-in-non-small-cell-lung-cancer-cells
#7
Hui-Ying Liu, Qing-Ran Li, Xue-Fang Cheng, Guang-Ji Wang, Hai-Ping Hao
Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the first rate-limiting step in converting nicotinamide to NAD(+), essential for a number of enzymes and regulatory proteins involved in a variety of cellular processes, including deacetylation enzyme SIRT1 which modulates several tumor suppressors such as p53 and FOXO. Herein we report that NQO1 substrates Tanshione IIA (TSA) and β-lapachone (β-lap) induced a rapid depletion of NAD(+) pool but adaptively a significant upregulation of NAMPT. NAMPT inhibition by FK866 at a nontoxic dose significantly enhanced NQO1-targeting agent-induced apoptotic cell death...
August 2016: Chinese Journal of Natural Medicines
https://www.readbyqxmd.com/read/27341379/synthesis-and-antitumor-activity-of-selenium-containing-quinone-based-triazoles-possessing-two-redox-centres-and-their%C3%A2-mechanistic-insights
#8
Eduardo H G da Cruz, Molly A Silvers, Guilherme A M Jardim, Jarbas M Resende, Bruno C Cavalcanti, Igor S Bomfim, Claudia Pessoa, Carlos A de Simone, Giancarlo V Botteselle, Antonio L Braga, Divya K Nair, Irishi N N Namboothiri, David A Boothman, Eufrânio N da Silva Júnior
UNLABELLED: Selenium-containing quinone-based 1,2,3-triazoles were synthesized using click chemistry, the copper catalyzed azide-alkyne 1,3-dipolar cycloaddition, and evaluated against six types of cancer cell lines: HL-60 (human promyelocytic leukemia cells), HCT-116 (human colon carcinoma cells), PC3 (human prostate cells), SF295 (human glioblastoma cells), MDA-MB-435 (melanoma cells) and OVCAR-8 (human ovarian carcinoma cells). Some compounds showed IC50 values < 0.3 μM. The cytotoxic potential of the quinones evaluated was also assayed using non-tumor cells, exemplified by peripheral blood mononuclear (PBMC), V79 and L929 cells...
October 21, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27242267/%C3%AE-lapachone-increases-phase-ii-antioxidant-enzyme-expression-via-nqo1-ampk-pi3k-nrf2-are-signaling-in-rat-primary-astrocytes
#9
Jin-Sun Park, Yu-Young Lee, Jisun Kim, Hyemyung Seo, Hee-Sun Kim
β-Lapachone (β-LAP) is a naturally occurring quinine that exerts a number of pharmacological actions including antibacterial, antifungal, antimalarial, and antitumor activities. In the present study, we investigated whether β-LAP has an antioxidant effect in rat primary astrocytes. β-LAP suppressed intracellular reactive oxygen species (ROS) production induced by hydrogen peroxide and inhibited astroglial cell death. It also increased astrocytic expression of phase II antioxidant enzymes such as heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1), manganese superoxide dismutase (MnSOD), and catalase...
August 2016: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/27196777/nqo1-mediated-tumor-selective-lethality-and-radiosensitization-for-head-and-neck-cancer
#10
Long-Shan Li, Srilakshmi Reddy, Zhen-Hua Lin, Shuangping Liu, Hyunsil Park, Stephen G Chun, William G Bornmann, Joel Thibodeaux, Jingsheng Yan, Gaurab Chakrabarti, Xian-Jin Xie, Baran D Sumer, David A Boothman, John S Yordy
UNLABELLED: Ionizing radiation (IR) is a key therapeutic regimen for many head and neck cancers (HNC). However, the 5-year overall survival rate for locally advanced HNCs is approximately 50% and better therapeutic efficacy is needed. NAD(P)H: quinone oxidoreductase 1 (NQO1) is overexpressed in many cancers, and β-lapachone (β-lap), a unique NQO1 bioactivatable drug, exploits this enzyme to release massive reactive oxygen species (ROS) that synergize with IR to kill by programmed necrosis...
July 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27048660/%C3%AE-lapachone-induces-nad-p-h-quinone-oxidoreductase-1-and-oxidative-stress-dependent-heat-shock-protein-90-cleavage-and-inhibits-tumor-growth-and-angiogenesis
#11
Yougen Wu, Xue Wang, Siyu Chang, Weiqiang Lu, Mingyao Liu, Xiufeng Pang
UNLABELLED: β-Lapachone [β-lap; 3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione] is a novel anticancer drug currently under investigation in phase I/II clinical trials. However, the mechanism underlying its clinical efficacy remains unclear. In this study, we found that β-lap provoked the cleavage of heat shock protein 90 (Hsp90) in NAD(P)H: quinone oxidoreductase-1 (NQO1)-expressing lung and prostate cancer cells as well as in primary human umbilical vein endothelial cells (HUVECs)...
June 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/26687450/overexpression-of-nad-p-h-quinone-oxidoreductase-1-nqo1-and-genomic-gain-of-the-nqo1-locus-modulates-breast-cancer-cell-sensitivity-to-quinones
#12
Christophe Glorieux, Juan Marcelo Sandoval, Nicolas Dejeans, Geneviève Ameye, Hélène Antoine Poirel, Julien Verrax, Pedro Buc Calderon
AIMS: Alterations in the expression of antioxidant enzymes are associated with changes in cancer cell sensitivity to chemotherapeutic drugs (menadione and β-lapachone). Mechanisms of acquisition of resistance to pro-oxidant drugs were investigated using a model of oxidative stress-resistant MCF-7 breast cancer cells (Resox cells). MAIN METHODS: FISH experiments were performed in tumor biopsy and breast cancer cells to characterize the pattern of the NQO1 gene. SNP-arrays were conducted to detect chromosomal imbalances...
January 15, 2016: Life Sciences
https://www.readbyqxmd.com/read/26602448/tumor-selective-use-of-dna-base-excision-repair-inhibition-in-pancreatic-cancer-using-the-nqo1-bioactivatable-drug-%C3%AE-lapachone
#13
Gaurab Chakrabarti, Molly A Silvers, Mariya Ilcheva, Yuliang Liu, Zachary R Moore, Xiuquan Luo, Jinming Gao, Glenda Anderson, Lili Liu, Venetia Sarode, David E Gerber, Sandeep Burma, Ralph J DeBerardinis, Stanton L Gerson, David A Boothman
UNLABELLED: Base excision repair (BER) is an essential pathway for pancreatic ductal adenocarcinoma (PDA) survival. Attempts to target this repair pathway have failed due to lack of tumor-selectivity and very limited efficacy. The NAD(P)H: Quinone Oxidoreductase 1 (NQO1) bioactivatable drug, ß-lapachone (ARQ761 in clinical form), can provide tumor-selective and enhanced synergy with BER inhibition. ß-Lapachone undergoes NQO1-dependent futile redox cycling, generating massive intracellular hydrogen peroxide levels and oxidative DNA lesions that stimulate poly(ADP-ribose) polymerase 1 (PARP1) hyperactivation...
November 25, 2015: Scientific Reports
https://www.readbyqxmd.com/read/26462257/targeting-glutamine-metabolism-sensitizes-pancreatic-cancer-to-parp-driven-metabolic-catastrophe-induced-by-%C3%A3-lapachone
#14
Gaurab Chakrabarti, Zachary R Moore, Xiuquan Luo, Mariya Ilcheva, Aktar Ali, Mahesh Padanad, Yunyun Zhou, Yang Xie, Sandeep Burma, Pier P Scaglioni, Lewis C Cantley, Ralph J DeBerardinis, Alec C Kimmelman, Costas A Lyssiotis, David A Boothman
BACKGROUND: Pancreatic ductal adenocarcinomas (PDA) activate a glutamine-dependent pathway of cytosolic nicotinamide adenine dinucleotide phosphate (NADPH) production to maintain redox homeostasis and support proliferation. Enzymes involved in this pathway (GLS1 (mitochondrial glutaminase 1), GOT1 (cytoplasmic glutamate oxaloacetate transaminase 1), and GOT2 (mitochondrial glutamate oxaloacetate transaminase 2)) are highly upregulated in PDA, and among these, inhibitors of GLS1 were recently deployed in clinical trials to target anabolic glutamine metabolism...
2015: Cancer & Metabolism
https://www.readbyqxmd.com/read/26188110/combinative-effects-of-%C3%AE-lapachone-and-apo866-on-pancreatic-cancer-cell-death-through-reactive-oxygen-species-production-and-parp-1-activation
#15
Caroline S Breton, Dominique Aubry, Vanessa Ginet, Julien Puyal, Mathieu Heulot, Christian Widmann, Michel A Duchosal, Aimable Nahimana
UNLABELLED: Pancreatic cancer (PC) is one of the most lethal human malignancies and a major health problem. Patients diagnosed with PC and treated with conventional approaches have an overall 5-year survival rate of less than 5%. Novel strategies are needed to treat this disease. Herein, we propose a combinatorial strategy that targets two unrelated metabolic enzymes overexpressed in PC cells: NAD(P)H: quinone oxidoreductase-1 (NQO1) and nicotinamide phosphoribosyl transferase (NAMPT) using β-lapachone (BL) and APO866, respectively...
September 2015: Biochimie
https://www.readbyqxmd.com/read/25590809/nampt-inhibition-sensitizes-pancreatic-adenocarcinoma-cells-to-tumor-selective-par-independent-metabolic-catastrophe-and-cell-death-induced-by-%C3%AE-lapachone
#16
Z Moore, G Chakrabarti, X Luo, A Ali, Z Hu, F J Fattah, R Vemireddy, R J DeBerardinis, R A Brekken, D A Boothman
Nicotinamide phosphoribosyltransferase (NAMPT) inhibitors (e.g., FK866) target the most active pathway of NAD(+) synthesis in tumor cells, but lack tumor-selectivity for use as a single agent. Reducing NAD(+) pools by inhibiting NAMPT primed pancreatic ductal adenocarcinoma (PDA) cells for poly(ADP ribose) polymerase (PARP1)-dependent cell death induced by the targeted cancer therapeutic, β-lapachone (β-lap, ARQ761), independent of poly(ADP ribose) (PAR) accumulation. β-Lap is bioactivated by NADPH:quinone oxidoreductase 1 (NQO1) in a futile redox cycle that consumes oxygen and generates high levels of reactive oxygen species (ROS) that cause extensive DNA damage and rapid PARP1-mediated NAD(+) consumption...
2015: Cell Death & Disease
https://www.readbyqxmd.com/read/25590579/eif2-kinases-mediate-%C3%AE-lapachone-toxicity-in-yeast-and-human-cancer-cells
#17
Mauricio Menacho-Márquez, Carlos J Rodríguez-Hernández, M Ángeles Villaronga, Jorge Pérez-Valle, José Gadea, Borja Belandia, José R Murguía
β-Lapachone (β-lap) is a novel anticancer agent that selectively induces cell death in human cancer cells, by activation of the NQO1 NAD(P)H dehydrogenase and radical oxygen species (ROS) generation. We characterized the gene expression profile of budding yeast cells treated with β-lap using cDNA microarrays. Genes involved in tolerance to oxidative stress were differentially expressed in β-lap treated cells. β-lap treatment generated reactive oxygen species (ROS), which were efficiently blocked by dicoumarol, an inhibitor of NADH dehydrogenases...
2015: Cell Cycle
https://www.readbyqxmd.com/read/25542645/esterase-activatable-%C3%AE-lapachone-prodrug-micelles-for-nqo1-targeted-lung-cancer-therapy
#18
Xinpeng Ma, Xiumei Huang, Zachary Moore, Gang Huang, Jessica A Kilgore, Yiguang Wang, Suntrea Hammer, Noelle S Williams, David A Boothman, Jinming Gao
UNLABELLED: Lung cancer is one of the most lethal forms of cancer and current chemotherapeutic strategies lack broad specificity and efficacy. Recently, β-lapachone (β-lap) was shown to be highly efficacious in killing non-small cell lung cancer (NSCLC) cells regardless of their p53, cell cycle and caspase status. Pre-clinical and clinical use of β-lap (clinical form, ARQ501 or 761) is hampered by poor pharmacokinetics and toxicity due to hemolytic anemia. Here, we report the development and preclinical evaluation of β-lap prodrug nanotherapeutics consisting of diester derivatives of β-lap encapsulated in biocompatible and biodegradable poly(ethylene glycol)-b-poly(D,L-lactic acid) (PEG-b-PLA) micelles...
February 28, 2015: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/25451262/%C3%AE-lapachone-attenuates-mitochondrial-dysfunction-in-melas-cybrid-cells
#19
Moon Hee Jeong, Jin Hwan Kim, Kang-Sik Seo, Tae Hwan Kwak, Woo Jin Park
Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a mitochondrial disease caused by mutations in the mitochondrial genome. This study investigated the efficacy of β-lapachone (β-lap), a natural quinone compound, in rescuing mitochondrial dysfunction in MELAS cybrid cells. β-Lap significantly restored energy production and mitochondrial membrane potential as well as normalized the elevated ROS level in MELAS cybrid cells. Additionally, β-lap reduced lactic acidosis and restored glucose uptake in the MELAS cybrid cells...
November 21, 2014: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/25448047/mechanistic-studies-of-cancer-cell-mitochondria-and-nqo1-mediated-redox-activation-of-beta-lapachone-a-potentially-novel-anticancer-agent
#20
COMPARATIVE STUDY
Jason Z Li, Yuebin Ke, Hara P Misra, Michael A Trush, Y Robert Li, Hong Zhu, Zhenquan Jia
UNLABELLED: Beta-lapachone (beta-Lp) derived from the Lapacho tree is a potentially novel anticancer agent currently under clinical trials. Previous studies suggested that redox activation of beta-Lp catalyzed by NAD(P)H: quinone oxidoreductase 1 (NQO1) accounted for its killing of cancer cells. However, the exact mechanisms of this effect remain largely unknown. Using chemiluminescence and electron paramagnetic resonance (EPR) spin-trapping techniques, this study for the first time demonstrated the real-time formation of ROS in the redox activation of beta-lapachone from cancer cells mediated by mitochondria and NQO1 in melanoma B16-F10 and hepatocellular carcinoma HepG2 cancer cells...
December 15, 2014: Toxicology and Applied Pharmacology
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